Vascular cell adhesion molecule-1 (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is expressed on activated, but not resting, endothelium. The integrin VLA-4(xcex14xcex21), which is expressed on many cell types including circulating lymphocytes, eosinophils, basophils, and monocytes, but not neutrophils, is the principal receptor for VCAM-1. Antibodies to VCAM-1 or VLA-4 can block the adhesion of these mononuclear leukocytes, as well as melanoma cells, to activated endothelium in vitro. Antibodies to either protein have been effective at inhibiting leukocyte infiltration and preventing tissue damage in several animal models of inflammation. Anti-VLA-4 monoclonal antibodies have been shown to block T-cell emigration in adjuvant-induced arthritis, prevent eosinophil accumulation and bronchoconstriction in models of asthma, and reduce paralysis and inhibit monocyte and lymphocyte infiltration in experimental autoimmune encephalitis (EAE). Anti-VCAM-1 monoclonal antibodies have been shown to prolong the survival time of cardiac allografts. Recent studies have demonstrated that anti-VLA-4 mAbs can prevent insulitis and diabetes in non-obese diabetic mice, and significantly attenuate inflammation in the cotton-top tamarin model of colitis. It has further been shown that VCAM is expressed on endothelial cells of inflamed colonic tissue in a TNB/ethanol rat model of inflammatory bowel disease (Gastroenterology 1999, 116, 874-883).
Thus, compounds which inhibit the interaction between xcex14-containing integrins and VCAM-1 will be useful as therapeutic agents for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), asthma, and inflammatory bowel disease (IBD).
It has been discovered that compounds of the formula I 
and the pharmaceutically acceptable salts thereof wherein R1, R2, R3, R5, and R6 are as defined below, inhibit the binding of VCAM-1 to VLA-4 and so would be useful in treating inflammatory diseases in which such binding contributes to the disease process.
As used in this specification, the term xe2x80x9chalogenxe2x80x9d means any of the four halogens, bromine, chlorine, fluorine, and iodine unless indicated otherwise. Preferred halogens are bromine, fluorine, and chlorine.
The term xe2x80x9clower alkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl and the like. Also, as used herein xe2x80x9clower alkylxe2x80x9d may be groups which are unsubstituted or substituted by one or more groups selected independently from cycloalkyl, nitro, aryloxy, aryl, hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, and amino or mono- or di- lower alkyl amino. Examples of substituted lower alkyl groups include 2-hydroxylethyl, 3-oxobutyl, cyanomethyl, and 2-nitropropyl. The term xe2x80x9cperfluoro lower alkylxe2x80x9d for purposes of R4, R22, or R23 means a substituted lower alkyl group as defined above which is a methyl or ethyl group where all of the hydrogens are substituted by fluoro, i.e. trifluoromethyl and pentafluoroethyl.
The term xe2x80x9clower alkenylxe2x80x9d means an alkylene group having from 2 to 10 carbon atoms with a double bond located between any two adjacent carbon atoms.
The term xe2x80x9ccycloalkylxe2x80x9d means an unsubstituted or substituted 3- to 7-membered carbacyclic ring. Substituents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino.
The term xe2x80x9clower alkoxyxe2x80x9d means a straight-chain or branched-chain alkoxy group containing a maximum of six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
The term xe2x80x9clower alkylthioxe2x80x9d means a lower alkyl group bonded to the rest of the molecule through a divalent sulfur atom, for example, a methyl mercapto or a isopropyl mercapto group. The term xe2x80x9clower alkylsulfinylxe2x80x9d means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in the sulfinyl group. The term xe2x80x9clower alkyl sulfonylxe2x80x9d means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in the sulfonyl group.
The term xe2x80x9carylxe2x80x9d means a mono- or bicylic aromatic group, such as phenyl or naphthyl, which is unsubstituted or substituted by conventional substituent groups. Preferred substituents are lower alkyl, lower alkoxy, hydroxy lower alkyl, hydroxy, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanoyl, aroyl, aryl alkynyl, lower alkynyl and lower alkanoylamino. Examples of aryl groups that may be used in accordance with this invention are phenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, m-hydroxy phenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, 1-naphthyl and the like.
The term xe2x80x9carylalkylxe2x80x9d means a lower alkyl group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl or heteroaryl group as herein defined. Any conventional aralkyl may be used in accordance with this invention, such as benzyl and the like.
The term xe2x80x9cheteroarylxe2x80x9d means an unsubstituted or substituted 5- or 6-membered monocyclic hetereoaromatic ring or a 9- or 10-membered bicyclic hetereoaromatic ring containing 1, 2, 3 or 4 hetereoatoms which are independently N, S or O. Examples of hetereoaryl rings are pyridine, benzimidazole, indole, imidazole, thiophene, isoquinoline, quinzoline and the like. Substituents as defined above for xe2x80x9carylxe2x80x9d are included in the definition of heteroaryl.
The term xe2x80x9clower alkoxycarbonylxe2x80x9d means a lower alkoxy group bonded to the rest of the molecule via a carbonyl group. Examples of alkoxycarbonyl groups are ethoxycarbonyl and the like.
The term xe2x80x9clower alkylcarbonyloxyxe2x80x9d means lower alkylcarbonyloxy groups bonded to the rest of the molecule via an oxygen atom, for example an acetoxy group. The term xe2x80x9cacyloxyxe2x80x9d has the same meaning.
The term xe2x80x9clower alkanoylxe2x80x9d means lower alkyl groups bonded to the rest of the molecule via a carbonyl group and embraces in the sense of the foregoing definition groups such as acetyl, propionyl and the like. The term xe2x80x9cperfluoro lower alkanoylxe2x80x9d means a perfluoro lower alkyl group (a substituted lower alkyl group where all of the hydrogens are substituted by fluoro, preferably trifluoromethyl or pentafluoroethyl bonded to the rest of the molecule via a carbonyl group. The term perfluoro lower alkanoylaminoxe2x80x9d means a perfluoro lower alkanoyl group bonded to the rest of the molecule via an amino group.
The term xe2x80x9clower alkylcarbonylaminoxe2x80x9d means lower alkylcarbonyl groups bonded to the rest of the molecule via a nitrogen atom, such as acetylamino. The term lower alkylaminocarbonylxe2x80x9d means lower alkyl amino groups bonded to the rest of the molecule via a carbonyl group. The term xe2x80x9carylaminocarbonylxe2x80x9d means aryl groups bonded to an amino group further bonded to the rest of the molecule via a carbonyl group.
The term xe2x80x9caroylxe2x80x9d means a mono- or bicyclic aryl or heteroaryl group bonded to the rest of the molecule via a carbonyl group. Examples of aroyl groups are benzoyl, 3-cyanobenzoyl, 2-naphthoyl, nicotinoyl, and the like.
Pharmaceutically acceptable salts are well known in the art and can be made by conventional methods taking into account the chemical nature of the compound. Examples of pharmaceutically acceptable salts for acidic compounds are alkali metal or alkaline earth metals such as sodium, potassium, calcium, magnesium, basic amines or basic amino acids, ammonium or alkyl ammonium salts. Particularly desirable salts for compounds of this invention are sodium salts. The sodium salt of any acid of this invention is easily obtained from the acid by treatment with sodium hydroxide. For basic compounds, examples are salts of inorganic or organic acids such as hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, citric, formic, fumaric, maleic, acetic, succinic, tartaric, methanesulfonic, and p-toluenesulfonic acid.
The present invention comprises a compound of the formula I: 
and the pharmaceutically acceptable salts thereof. In accordance with the invention, R1 is a group Y-1, Y-2 or Y-3 as described below:
R1 is Y-1, a group of the formula: 
wherein: R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R22 and R23 is other than hydrogen, and R24 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen,
R1 is Y-2, a five or six membered heteroaromatic ring bonded via a carbon atom to the amide carbonyl wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and one or two atoms of said ring are independently substituted by lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of said substituted atoms is adjacent to the carbon atom bonded to the amide carbonyl,
R1 is Y-3, a 3-7 membered ring of the formula: 
wherein: R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R26xe2x80x94(CH2)exe2x80x94, R26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R26 is a group of formula xe2x80x94NR28R29, wherein R28 is hydrogen or lower alkyl, R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl, or R28 and R29, taken together with the attached nitrogen atom, form a 4, 5 or 6-membered saturated heterocyclic ring optionally containing one additional heteroatom selected from O, S, and Nxe2x80x94R40, Q is xe2x80x94(CH2)fOxe2x80x94, xe2x80x94(CH2)fSxe2x80x94, xe2x80x94(CH2)fN(R27)xe2x80x94, xe2x80x94(CH2)fxe2x80x94, R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, R40 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, the carbon atoms in the ring are unsubstituted or substituted by lower alkyl or halogen, e is an integer from 0 to 4, and f is an integer from 0 to 3; R2 is hydrogen or lower alkyl substituted lower alkyl arylalkyl, or aryl; R3 is hydrogen or lower alkyl, substituted lower alkyl, arylalkyl, or aryl; R4 is hydrogen, lower alkyl, substituted lower alkyl (such as perfluoro lower alkyl), or aryl; R5 is hydrogen, lower alkyl, chloro, or lower alkoxy; R6 is hydrogen, lower alkyl, lower alkyl carbonyloxy lower alkyl, substituted lower alkyl, or R6 is a group of formula P-3: 
wherein: R32 is hydrogen or lower alky, R33 is hydrogen, lower alkyl, aryl, R34 is hydrogen or lower alkyl, h is an integer from 0 to 2, g is an integer from 0 to 2, the sum of h and g is 1 to 3; or R6 is a group of formula P-4: 
wherein: R32, g, and h are as previously defined, Qxe2x80x2 is O, S, xe2x80x94(CH2)jxe2x80x94, or a group of the formula Nxe2x80x94R35R35 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, j is 0, 1 or 2
The compounds of the invention can exist as stereoisomers and diastereomers, all of which are encompassed within the scope of the present invention.
The compounds of the invention inhibit the binding of VCAM-1 and fibronectin to VLA-4 on circulating lymphocytes, eosinophils, basophils, and monocytes (xe2x80x9cVLA-4-expressing cellsxe2x80x9d). The binding of VCAM-1 and fibronectin to VLA-4 on such cells is known to be implicated in certain disease states, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and particularly in the binding of eosinophils to airway endothelium which contributes to the cause of the lung inflammation which occurs in asthma. Thus, the compounds of the present invention are useful for the treatment of asthma.
On the basis of their capability of inhibiting binding of VCAM-1 and fibronectin to VLA-4 on circulating lymphocytes, eosinophils, basophils, and monocytes, the compounds of the invention can be used as medicament for the treatment of disorders which are known to be associated with such binding. Examples of such disorders are rheumatoid arthritis, multiple sclerosis, asthma, and inflammatory bowel disease. The compounds of the invention are preferably used in the treatment of diseases which involve pulmonary inflammation, such as asthma. The pulmonary inflammation which occurs in asthma is related to the activation and lung infiltration of eosinophils, monocytes and lymphocytes which have been activated by some asthma-triggering event or substance.
Furthermore, compounds of the invention also inhibit the binding of MadCAM to the cellular receptor alpha4-beta7, also known as LPAM, which is expressed on lymphocytes, eosinophiles and T-cells. While the precise role of alpha4-beta7 interaction with various ligands in inflammatory conditions such as asthma is not completely understood, compounds of the invention which inhibit both alpha4-beta1 and alpha4-beta7 receptor binding are particularly effective in animal models of asthma. Furthermore work with monoclonal antibodies to alpha4-beta7 indicate that compounds which inhibit alpha4-beta7 binding to MadCAM are useful for the treatment of inflammatory bowel disease. They would also be useful in the treatment of other diseases in which such binding is implicated as a cause of disease damage or symptoms.
The compounds of the invention can be administered orally, rectally, or parentally, e.g., intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually, or as opthalmalogical preparations, or as an aerosol in the case of pulmonary inflammation. Capsules, tablets, suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, salves or spray solutions are examples of administration forms.
Intravenous, intramuscular, oral or inhalation administration is a preferred form of use. The dosages in which the compounds of the invention are administered in effective amounts depending on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of administration. Dosages may be determined by any conventional means, e.g., by dose-limiting clinical trials. Thus, the invention further comprises a method of treating a host suffering from a disease in which VCAM-1 or fibronectin binding to VLA-4-expressing cells is a causative factor in the disease symptoms or damage by administering an amount of a compound of the invention sufficient to inhibit VCAM-1 or fibronectin binding to VLA-4-expressing cells so that said symptoms or said damage is reduced. In general, dosages of about 0.1-100 mg/kg body weight per day are preferred, with dosages of 1-25 mg/kg per day being particularly preferred, and dosages of 1-10 mg/kg body weight per day being espeically preferred.
The invention further comprises pharmaceutical compositions which contain a pharmaceutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. Such compositions may be formulated by any conventional means. Tablets or granulates can contain a series of binders, fillers, carriers or diluents. Liquid compositions can be, for example, in the form of a sterile water-miscible solution. Capsules can contain a filler or thickener in addition to the active ingredient. Furthermore, flavour-improving additives as well as substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and other additives can also be present.
The previously mentioned carrier materials and diluents can comprise any conventional pharmaceutically acceptable organic or inorganic substances, e.g., water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like.
Oral unit dosage forms, such as tablets and capsules, preferably contain from 25 mg to 1000 mg of a compound of the invention.
Generally the compounds of the present invention can be prepared from suitable phenylalanine derivatives via a palladium catalyzed reaction with a 5-halo-2,4-dioxopyrimidone.
As shown in Reaction Scheme 1, a 4-iodo- or 4-bromophenylalanine derivative such as 1, is converted into a protected phenylalanine derivative 2 in which R5xe2x80x2 is hydrogen, chloro, lower alkyl or lower alkoxy, P1 is a standard nitrogen protecting group such as a Boc, or carbobenzyloxy group and P2 is lower alkyl or substituted lower alkyl selected appropriately to serve as a protecting group or an element of a prodrug. The group P2 can be introduced by conventional means familiar to those who practice peptide chemistry. The order of the addition of P1 and P2 is not critical and will depend on the particular choice of reagents. A discussion of the use and introduction of protecting groups is provided in Theodora W. Greene and Peter G. M. Wuts., Protecting Groups in Organic Synthesis, Wiley Interscience, New York, 1991. Alternatively, a compound of formula 1 may be converted to a compound of formula 4, in which R1xe2x80x2 represents a component of an acyl group of the invention. A convenient method is to introduce the ester group P2 first, followed by a coupling reaction of the free amine using conventional peptide coupling reagents, for example HBTU in the presence of a tertiary amine base such as diethylisopropylamine. Again, the particular choice of reagents may dictate altering the sequence of the introduction of R1xe2x80x2 and P2. Conversion of compounds of formula 2 or 4 to derivatives 3 or 5, in which M represents a substituted tin or boron atom, can be effected by treatment with a suitable species, for example hexamethylditin, hexabutylditin or a tetraalkoxydiboron in the presence of a source of palladium zero. The methodology is outlined and referenced in F. Diederich and P. J. Stang, ed, Metal Catalyzed Cross Coupling Reactions, Wiley-VCH, Weinheim, Germany, 1998. 
Pyrimidine-2,4-diones (uracil derivatives) of formula 6 wherein R4xe2x80x2 is hydrogen, lower alkyl or perfluorolower alkyl are well known in the literature or can be made by known methods. 1,3-Disubstituted pyrimidin-2,4-diones of formula 7 wherein R2xe2x80x2 and R3xe2x80x2 are lower alkyl, aryl lower alkyl or aryl are also known compounds or can be prepared by standard procedures. Papers reporting synthetic methods for their construction include: Shigeo Senda, et al. Chem. Pharm. Bull. 1974, 22, 189-195, Chem Pharm Bull 1972, 20, 1389-1396, and Yasuo Morita, et al., Chem Comm. 1997 359-360. For the case where R2xe2x80x2 and R3xe2x80x2 are lower alkyl or aryl lower alkyl, compounds of formula 7 are available by alkylation of compounds of formula 6 by treatment with an alkylating agents such as iodomethane, benzylbromide, allyl bromide in the presence of a base such as potassium carbonate and optionally, a phase transfer catalyst. For less reactive alkylating agents, it may be necessary to use a stronger base such as an alkali metal hydroxide and to heat the reaction mixture. Compounds of formula 6 or 7 as defined above may be halogenated in the 5-position by treatment with conventional halogenating reagents such as bromine, N-iodosuccinimide or N-bromosuccinimide in a suitable solvent such as glacial acetic acid or aqueous acetic acid to give halopyrimidines of formula 8, X=Br or I, R2xe2x80x2, and R3xe2x80x2, are independently hydrogen, lower alkyl, aryl lower alkyl or aryl, R4xe2x80x2=hydrogen, lower alkyl or perfluorolower alkyl. 
As shown in Reaction Scheme 3, the compound of formula 8 can be used in a palladium catalyzed coupling reaction with a phenylalanine derivative of formula 3 or 5. For example, when M is a substituted tin, treatment of a mixture of 8 and the phenylalanine of formula 3 or 5 with a source of palladium zero such as tetraakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride in the presence of an inert solvent such as DMF at a temperature of between room temperature and 100xc2x0 C. gives a compound of formula 9 or 10. Compounds of structure 9 may be converted into compounds of structure 10 by removal of the protecting group P1, which may be accomplished by conventional means depending on the selection of P1. For example, if P1 is a Boc group, it may be removed by treatment with a strong acid, such as trifluoroacetic acid, optionally in the presence of a solvent such as dichloromethane and a scavenging agent. The resulting free amine may then be acylated with an acid of the formula R1xe2x80x2CO2H using conventional peptide coupling techniques. For example, by treatment with HBTU in the presence of a tertiary amine base such as diethylisopropylamine in the presence of an aprotic solvent such as DMF to give the compound of structure 10.
If the free acid 11 is the desired end product, the ester group, P2 may be removed by conventional means. For example, in the case that P2 is lower alkyl, for example methyl, it may be removed by treatment with an alkali metal hydroxide, for example lithium hydroxide, in a suitable solvent, for example aqueous THF optionally containing methanol to assist with solubility. If P2 were a benzyl or substituted benzyl group, it could also be removed by catalytic hydrogenation over a noble metal catalyst, for example palladium on carbon. 
Alternatively, as shown in Reaction Scheme 4, a compound of structure 8, wherein X is bromide or iodide, may be converted to a species of formula 12, in which Mxe2x80x2 represents a substituted tin, boron or zinc atom. In the case of the tin or boron derivatives, in which Mxe2x80x2 represents a substituted tin or boron atom, the conversion can be effected by treatment with a suitable species, for 
example hexamethylditin, hexabutylditin or a tetaalkoxydiboron in the presence of a source of palladium zero. For the formation of the zinc derivative, 12, Mxe2x80x2=Zn(halogen), conversion may be effected by treatment of the compound of formula 8, X=I with a source of activated zinc metal in a suitable inert solvent, for example dimethylacetamide at a temperature of from room temperature to 100xc2x0 C. until conversion is complete to give a compound of formula 12, Mxe2x80x2=Zn(halogen). These compounds of formula 12 can be reacted with a 4-substituted phenylalanine derivative of formula 4xe2x80x2 in which Xxe2x80x2 is iodo, bromo, or trifluoromethylsulfonyloxy in the presence of a source of palladium zero to give a compound of formula 10xe2x80x2. In the case where the ester group represented by P2 is not part of the targeted compound, it can be removed using ester hydrolysis procedures appropriate to the particular P2. For example, where P2 is lower alkyl, for example methyl, it can be removed by standard base hydrolysis using an alkali metal hydroxide, for example, lithium hydroxide. In a variation on this procedure, it may be desirable to carry a protecting group through the coupling reaction and substitute it at a later time. In this case, a compound of formula 2xe2x80x2, in which P1xe2x80x2 is lower alkoxycarbonyl or benzyloxycarbonyl and Xxe2x80x2 is as defined above, may be coupled with a pyrimidinedione of structure 12 to give a compound of structure 9xe2x80x2 which in turn may be converted to a compound of the invention using the general procedures noted above in reaction scheme 3.
An alternative route to compounds of this invention, as shown in Reaction Scheme 5, which is particularly applicable to compounds in which R5xe2x80x2 is other than hydrogen, is to build an aldedyde of formula 14. This can be accomplished by reacting a compound of formula 12 with a compound of formula 13, in which R5xe2x80x2 represents lower alkyl or lower alkoxy, and Xxe2x80x3 represents an iodide, bromide, of trifluoromethylsulfonyloxy moiety and R8 represents a protected alcohol or aldehyde. For alcohols, suitable protecting groups include silyl ethers, benzyl ethers. Aldehydes, may be protected as their acetal derivatives. The compound of formula 12 can be converted to an aldehyde of formula 15 by convertional steps which, when R8 is an alcohol, would involve protecting group removal, if necessary, followed by oxidation. Any of the common reagents for the selective oxidation of primary benzyl alcohols to aldehydes may be employed, for example, treatment with activated manganese dioxide in an inert solvent. In the case where R8 represents a protected aldehyde, conversion to an aldehyde of formula 15 can be carried out by a suitable protecting group removal, for example hydrolysis of an acetal with dilute acid. Reaction of 15 to give a dehydroamino acid of formula 16 can be effected by treatment with a Wittig reagent of formula 17 in which P1xe2x80x2 is lower alkoxycarbonyl or benzyloxycarbonyl and P2 is as defined above. For example treatment of 15 with (xc2x1)-N-(benzyloxycarbonyl)-xcex1-phosphonoglycine trimethyl ester in the presence of a suitable base for example tetramethylguanidine leads directly to a dehydroamino acid of formula 16, P2=methyl and P1xe2x80x2=benzyloxycarbonyl. Enantioselective reduction of 16 to the L-amino acid 18 can be effected by use of a number of reducing agents suitable for the purpose, for example, the recently described ethyl-DuPHOS rhodium reagent (Burk, M. J., Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125) using essentially the literature procedure. Further conversion of 18 to the compounds of the invention can be carried out using the general procedures discussed above. 
In one embodiment, the N-acyl group, R1xe2x80x2 of structure 11, is derived from a 2-subsituted benzoic acid. Appropriate 2-substituted benzoic acids are either commercially available or can be prepared by conventional means. For example ortho-substituted aryl iodides or triflates may be carbonylated in the presence of carbon monoxide and a suitable palladium catalyst. The preparation of such iodide or triflate intermediates is dependent on the particular substitution pattern desired and they may be obtained by direct iodination or diazotization of an aniline followed by treatment with a source of iodide for example, potassium iodide. Triflates may be derived from the corresponding phenols by conventional means such as by treatment with trifluoromethane sulfonic anhydride in the presence of a base such as triethylamine or diisopropylethylamine in an inert solvent. As shown in Reaction Scheme 6, one other means of obtaining ortho-substituted benzoic acids involves treatment of an 2-methoxyphenyloxazoline derivative such as compound 19, Z1 and Z2=hydrogen, alkyl, chloro, perfluoroalkyl, lower alkoxy with an alkyl Grignard reagent followed by hydrolysis of the oxazoline ring following the general procedure described by Meyers, A. I., Gabel, R., Mihelick, E. D, J. Org. Chem. 1978, 43, 1372-1379, to give an acid of formula 20. 2- or 2,6-Disubstituted benzonitriles also serve as convenient precursors to the corresponding benzoic acids. In the case of highly hindered nitrites, for example 2-chloro-6-methylbenzonitrile, conventional hydrolysis under acidic or basic conditions is difficult and better results are obtained by DIBAL reduction to the corresponding benzaldehyde followed by oxidation using a chromium based oxidizing reagent. Other methods are exemplified in Chen, et al., WO 9910312. 
Referring now to Reaction Scheme 7, cyclic acids of formula 23 are known compounds or can be prepared using standard methodologies. For the preparation of substituted alkyl- or cycloalkylcarboxylic acids, alkylation reactions can be employed using an alkali metal dianion of the acid or monoanion of the corresponding ester. For example, a cycloalkyl carboxylic acid ester of formula 21 can be treated with a strong base, for example, lithium diisopropylamide in an inert solvent, for example THF followed by addition of group R41-Lv wherein R41, represents a desired side chain, such as a substituted benzyl, lower alkyl, lower alkoxy alkyl, azidolower alkyl and the like and Lv represents a leaving group such as a bromide, iodide, mesylate or similar group known to participate in ester enolate alkylation reactions. The product ester 22 may be hydrolyzed to the acid 23 using alkali metal hydroxide in a suitable solvent, for example aqueous alcohol. Depending on the nature of R41, and the eventual target, the compound 23 may be coupled to an amine such as compound 1 and converted to the target directly or R41, may be subject to further manipulation at a suitable point in the synthesis. For example, if R41 is an azido lower alkyl moiety, the azide may be reduced using for example a trialkyl phosphine reagent followed by functionalization of the product amine by alkylation, acylation, sulfonylation and related procedures well known to those skilled in the art. If R41 incorporates a leaving group, for example, a termninal bromine atom, this group may be displaced by an appropriate nucleophile, for example, sodium methyl mercaptide to give in this case, a thioether which may be the desired product or can be itself further manipulated, for example by oxidation to a sulfoxide or sulfone using standard reaction conditions. Other nucleophiles which may be employed to produce intermediates leading to compounds of this invention include: sodium cyanide, sodium methoxide, sodium azide, morpholine and others. When R41, incorporates a ketal group, this group may be hydrolzyed at a convenient point in the synthesis to provide a keto group. This group in turn may be further manipulated, for example by reduction to an alcohol or conversion to derivative such as an oxime.
Examples of the application of these methods to the synthesis of compounds of formula 23 are provided in Chen, et al. WO 9910313. 
In general, ortho-substituted aromatic acids needed for the preparation of compounds in which R1=Y-1 can be prepared as exemplified in Chen, et al., WO9910312.
For the synthesis of 2-chloro-6-alkylbenzoic acids of formula 28, wherein R43 is lower alkyl, the procedure described in Reaction Scheme 8 is particularly suitable. Thus, a commercially available aldehyde of formula 24 is converted to the imine 25 wherein R42 is lower alkyl, preferably butyl, by treatment with butylamine in an inert, hydrophobic organic solvent, for example heptane. The resulting compound of formula 25 is treated with an excess of a Grignard derivative 26 in an inert solvent, for example THF, followed by acid treatment during the workup to give an aldehyde of formula 27. Oxidation of 27 to an acid of formula 28 can be carried out by conventional means, for example by treatment of a solution of 27 in a suitable solvent such as aqueous acetonitrile with sodium chlorite and 30% hydrogen peroxide at or below room temperature. 
It may be desirable to prepare prodrug esters of the compounds of this invention for which it would be more convenient to introduce the ester moiety at the end of the synthesis. For this purpose, a variety of common techniques for the formation of esters from carboxylic acids may be employed. Typical methods which may be useful would include, coupling of an alcohol to the carboxylic acid in the presence of acid, for example hydrochloric acid, a procedure commonly known as a Fisher esterification. Alternatively, a diimide mediated coupling between the carboxylic acid and an alcohol may be employed with the optional use of a promoter such as 4,4-dimethylaminopyridine. A typical diimide is dicyclohexylcarbodiimide. Another alternative is to treat the carboxylic acid with a reactive alkyl halide, for example, an alkyl iodide or an acyloxymethyl chloride in the presence of a base, for example sodium bicarbonate and an inert solvent, for example DMF. The particular choice of method will be determined by the nature of the particular combination of carboxylic acid and desired ester moiety and will be apparent to one skilled in the art. Ester groups which may constitute prodrugs may be introduced at any convenient point in the synthesis. For example the group P2 in formula 1 may represent a desirable prodrug ester and be retained in the final product.
The preferred compounds of this invention are compounds of formula Ia. Formula Ia is the same as Formula I as follows: 
wherein R1 is a group of the formula Y-1
wherein R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R22 and R23 is other than hydrogen; and R24 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen; or R1 is a five or six membered heteroaromatic ring bonded via a carbon atom to the amide carbonyl wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and one or two atoms of said ring are independently substituted by lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of said substituted atoms is adjacent to the carbon atom bonded to the amide carbonyl; or R1 is a group of formula Y-3 which is a 3-7 membered ring of the formula: 
wherein R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R26xe2x80x94(CH2)exe2x80x94, R26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio , lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R26 is a group of formula xe2x80x94NR28R29, wherein R28 is hydrogen or lower alkyl, R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylamninocarbonyl, arylaminocarbonyl; or R28 and R29, taken together with the attached nitrogen atom, form a 4, 5 or 6-membered saturated heterocyclic ring optionally containing one additional heteroatom selected from O, S, and Nxe2x80x94R40, Q is xe2x80x94(CH2)fOxe2x80x94, xe2x80x94(CH2)fSxe2x80x94, xe2x80x94(CH2)fN(R27)xe2x80x94, xe2x80x94(CH2)fxe2x80x94, R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, R40 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, the carbon atoms in the ring are unsubstituted or substituted by lower alkyl or halogen, e is an integer from 0 to 4, and f is an integer from 0 to 3. In Formula Ia, R2 is hydrogen or lower alkyl, substituted lower alkyl, or aryl, R3 is hydrogen or lower alkyl, substituted lower alkyl, or aryl, R4 is hydrogen, lower alkyl, perfluoro lower alkyl, or aryl, R5 is hydrogen, lower alkyl, chloro, or lower alkoxy. As in Formula I, R6 is hydrogen, lower alkyl, lower alkyl carbonyloxy lower alkyl, substituted lower alkyl,or R6 is a group of formula P-3. Preferably, R4 is hydrogen, lower alkyl, or perfluoro lower alkyl. 
wherein R32 is hydrogen or lower alkyl; R33 is hydrogen, lower alkyl, aryl; R34 is hydrogen or lower alkyl; h is an integer from 0 to 2; g is an integer from 0 to 2; the sum of h and g is 1 to 3;or or R6 is a group of formula P-4: 
wherein R32, g, and h are as previously defined; Qxe2x80x2 is O, S, xe2x80x94(CH2)jxe2x80x94, or a group of the formula Nxe2x80x94R35; wherein R35 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl; j is 0, 1 or 2, or its pharmaceutically acceptable salts.
Each of the compounds of this invention is also contemplated in its pharmaceutically acceptable salt form.
In a preferred embodiment of Formula I or Formula Ia, R1 is a group of the formula Y-1 as defined in formula I and R22 and R23 are independently lower alkyl or halogen; and R24 is hydrogen. In another preferred embodiment, R1 is a group of the formula Y-1 as defined in formula I and R22 and R23 are independently hydrogen or halogen; and R24 is lower alkoxy.
Another preferred embodiment of Formula I or Formula Ia features R1 as a group of formula Y-3 as defined in formula I where R25 is a group of formula R26xe2x80x94(CH2)exe2x80x94, wherein R26 is lower alkoxy, Q is xe2x80x94(CH2)fxe2x80x94, e is an integer from 0 to 4, and f is an integer from 0 to 3.
Also part of this invention is a compound of the formula Ib: 
where R1 is as defined in formula I, R2 is lower alkyl; R3 is lower alkyl; R4 is hydrogen, perfluoro lower alkyl, or lower alkyl, R5 is hydrogen or lower alkyl; and R6 is hydrogen, lower alkyl, lower alkyl carbonyloxylower alkyl, a group of formula P-3 as defined in formula I or a group of formula P-4 as defined in formula I. It is preferred that R1 is a group of the formula Y-1 as defined in formula I where R22 and R23 are independently perfluoro lower alkyl, lower alkyl, or halogen; and R24 is hydrogen.
When R1 is a group of the formula Y-1 as defined in the preceding paragraph, it is preferred that i) R2 and R3 are lower alkyl; R4 is hydrogen or lower alkyl, and R5 and R6 are hydrogen, or ii) R2 and R3 are lower alkyl; R4 is hydrogen or lower alkyl, R5 is hydrogen, and R6 is hydrogen, lower alkyl, lower alkyl carbonyloxy lower alkyl, or R6 is a group of formula P-3 as defined in formula I or R6 is a group of formula P-4 as defined in formula I(preferably R35 is hydrogen), especially where R6 is lower alkyl, lower alkyl carbonyloxy lower alkyl, a group of the formula P-3 wherein R32 is hydrogen; R33 and R34 are lower alkyl; h is 1; and g is 0, or a group of the formula P-4 wherein R32 is hydrogen; h is 1; g is 0; and Qxe2x80x2 is O, or iii) R2 and R3 are lower alkyl; R4 is perfluoro lower alkyl, and R5 and R6 are hydrogen. or iv) R2 and R3 are lower alkyl; R4 is hydrogen; R5 is lower alkyl, and R6 is hydrogen.
In compounds of this invention of the formula Ib, 
where R1 is as defined in formula I, R2 is lower alkyl; R3 is lower alkyl; R4 is hydrogen, perfluoro lower alkyl, or lower alkyl, R5 is hydrogen or lower alkyl; and R6 is hydrogen, lower alkyl, lower alkyl carbonyloxy lower alkyl, a group of formula P-3 as defined in formula I or a group of formula P-4 as defined in formula I (preferably R35 is hydrogen), it is also preferred that R1 is a group of formula Y-3 as defined in formula I, where R25 is a group of formula R26xe2x80x94(CH2)exe2x80x94, wherein R26 is lower alkoxy, Q is xe2x80x94(CH2)fxe2x80x94, e is an integer from 0 to 4, and f is an integer from 0 to 3. In such compounds, it is preferred that R2 and R3 are lower alkyl, R4 is hydrogen or lower alkyl; and R5 and R6 are hydrogen.
In compounds of this invention of the formula Ib: 
where R1 is as defined in formula I, R2 is lower alkyl; R3 is lower alkyl; R4 is hydrogen, perfluoro lower alkyl, or lower alkyl, R5 is hydrogen or lower alkyl; and R6 is hydrogen, lower alkyl, lower alkyl carbonyloxy lower alkyl, a group of formula P-3 as defined in formula I or a group of formula P-4 as defined in formula I, it is particularly preferred that R2 and R3 are lower alkyl; and R4, R5 and R6 are hydrogen, especially where R1 is a group of the formula Y-1 as defined in formula I, preferably where R22 and R23 are independently lower alkyl or halogen; and R24 is hydrogen or where R22 and R23 are independently hydrogen or halogen; and R24 is lower alkoxy.
In the compound of the preceding paragraph where R2 and R3 are lower alkyl; and R4, R5 and R6 are hydrogen it is also preferred that R1 is a five or six membered heteroaromatic ring bonded via a carbon atom to the amide carbonyl wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and one or two atoms of said ring are independently substituted by lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of said substituted atoms is adjacent to the carbon atom bonded to the amide carbonyl.
In the compound of the above paragraph where R2 and R3 are lower alkyl; and R4, R5 and R6 are hydrogen it is also preferred that R1 is a group of formula the Y-3 as defined in formula I, preferably where R25 is a group of formula R26xe2x80x94(CH2)exe2x80x94, wherein R26 is lower alkoxy, Q is xe2x80x94(CH2)fxe2x80x94, e is an integer from 0 to 4, and f is an integer from 0 to3.
A preferred embodiment of the present invention is a compound of the formula I: 
wherein R1 is a group of the formula Y-1
wherein R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R22 and R23 is other than hydrogen; and R24 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen; R2 is lower alkyl; R3 is lower alkyl; R4 is hydrogen, or lower alkyl; R5 is hydrogen; and R6 is hydrogen.
A more preferred embodiment of the present invention is a compound of formula I above wherein R1 is a group of the formula Y-1
wherein R22 and R23 are independently hydrogen, lower alkyl or halogen, R24 is hydrogen or lower alkoxy; R2 is lower alkyl; R3 is lower alkyl; R4 is hydrogen, or lower alkyl; R5 is hydrogen; and R6 is lower alkyl, lower alkyl carbonyloxy lower alkyl, or preferably hydrogen.
Another preferred embodiment of the present invention is a compound of Formula I above wherein R1 is a five or six membered heteroaromatic ring bonded via a carbon atom to the amide carbonyl wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and one or two atoms of said ring are independently substituted by lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of said substituted atoms is adjacent to the carbon atom bonded to the amide carbonyl; R2 is lower alkyl; R3 is lower alkyl; R4 is hydrogen, perfluoro lower alkyl, or lower alkyl; R5 is hydrogen; and R6 is hydrogen.
Another preferred embodiment of the present invention is a compound of Formula I above wherein R1 is a group of formula Y-3 which is a 3-7 membered ring of the formula: 
wherein R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R26xe2x80x94(CH2)exe2x80x94, R26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R26 is a group of formulaxe2x80x94NR28R29, wherein R28 is hydrogen or lower alkyl, R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl; or R28 and R29, taken together with the attached nitrogen atom, form a 4, 5 or 6-membered saturated heterocyclic ring optionally containing one additional heteroatom selected from O, S, and Nxe2x80x94R40,Q is xe2x80x94(CH2)fOxe2x80x94, xe2x80x94(CH2)fSxe2x80x94, xe2x80x94(CH2)fN(R27)xe2x80x94, xe2x80x94(CH2)fxe2x80x94, R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, R40 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonylthe carbon atoms in the ring are unsubstituted or substituted by lower alkyl or halogen,e is an integer from 0 to 4, and f is an integer from 0 to 3; R2 is lower alkyl; R3 is lower alkyl; R4 is hydrogen, perfluoro lower alkyl, or lower alkyl; R5 is hydrogen; and R is hydrogen.
A more preferred embodiment of the present invention is a compound of formula I above wherein R1 is a group of formula Y-3 which is a 3-7 membered ring of the formula: 
wherein R25 is a group of formula R26xe2x80x94(CH2)exe2x80x94, wherein R26 is lower alkoxy, Q is xe2x80x94(CH2)fxe2x80x94, e is an integer from 0 to 4, and f is an integer from 0 to 3; R2 is lower alkyl; R3 is lower alkyl; R4 is hydrogen, perfluoro lower alkyl, or lower alkyl; R5 is hydrogen; and R6 is hydrogen.